Topical formulations and treatments

ABSTRACT

The present invention provides topical dosages and formulations of lidocaine and pharmaceutically acceptable salts thereof, which are efficacious, chemically stable and physiologically balanced for safety and efficacy, particularly for debridement pain, and increase the duration of pain relief, and thereby provide more effective treatment to chronic open wounds, particularly those in non-mucosal tissue.

FIELD OF THE INVENTION

The present invention relates to topical dosage forms and formulationsof lidocaine. These formulations are therapeutically effective forinducing local anesthesia, chemically stable, and particularly usefulfor the relief of debridement pain of chronic open wounds.

BACKGROUND OF THE INVENTION

In the Unites States chronic wounds affect the nation's population andhealth care costs. It has been estimated that more than six millionpeople suffer from chronic wounds, deriving from decubitus, vascular,inflammatory, and rheumatologic sources. The number of such people isexpected to increase due to the growth in the elderly population and theprevalence of diabetes in such population. Concurrently, the growingpopulation with chronic wounds leads to an increase in medical costs asevidenced by a study showing that chronic wound care cost $9.7 billionin 2004. Therefore, an improvement of chronic wound treatment in medicalprocedures would address a number of social and medical issues.

One of the problems accompanying chronic wound treatment is associatedwith pain that a patient may suffer. It has been found that up to 69% ofpatients with chronic venous ulcers suffer significant pain. Pain may beeven more severe for patients suffering from an underlying diseaseprocess such as diabetic peripheral neuropathy.

For appropriate pain management in patients with chronic wounds, it isnecessary to determine the source of the pain, i.e., whether the painarises from the wound itself or from the underlying disease. If the painis due to the wound itself, treatment of the wound with moistureretentive wound dressings, controlling infection, assuring adequatecirculation, and reducing edema are a typical protocol to relieve thepain. If the pain is associated with an underlying disease such asdiabetes mellitus, successful pain management requires special care aswell as primary care since pain is often worsened by wound treatments,such as dressing changes as well as vulnerable periwound skin. In fact,one study showed that it was a major concern for 43% of medicalpractitioners to control acute pain during wound debridement. Anotherstudy confirmed that wound treatments themselves such as dressingremoval, debridement, and inappropriate dressing selection promote woundrelated pain. Therefore, it is necessary to use analgesics oranesthetics during wound treatments.

Analgesics are categorized into two types, narcotics and non-narcotics,and are frequently used for long-term pain relief in patients withchronic wounds. However, the long-term use of either narcotics ornon-narcotic can lead to tolerance and necessity of dose escalation. Theformer leads to addiction, dependence and tolerance while the lattercauses a ceiling effect.

Topical anesthetics are widely used to numb the skin and to relive painin medical and surgical procedures in anesthesia, ophthalmology,otorhinolaryngology, dentistry, urology, and aesthetic surgery. Amongtopical anesthetics, lidocaine, tetracaine, benzocaine, and prilocainein a cream, ointment, or gel are commonly available prescription and/orover-the-counter (OTC) topical anesthetics.

Of the anesthetics, both lidocaine and benzocaine are most popular andcommonly used in medical procedures. Lidocaine absorbs more quicklywhere applied due to its higher water-solubility and tends to lastlonger than benzocaine. Thus, benzocaine is often found in sunburn andoral ulcer products whereas lidocaine is more often found inprescription medications. Unfortunately, lidocaine is most effectivelyabsorbed through mucosal surfaces, not skin.

Lidocaine HCl has been used in topical dosage forms for topicalanesthesia in mucosal tissues and could be attractive, particularly ifit is used as a topical anesthetic in non-mucosal tissues to reduce thedebridement pain arising from chronic open wounds.

For example, compositions and methods for treating a disease, such asinfection, pain or inflammation are reported in PCT InternationalPublication No. WO 2011/153334 to Trilogic Pharma LLC. The compositioncomprises water, polyethylene glycol and/or ethyl alcohol, poloxamer,xanthan gum and active ingredients. Among various active ingredients,benzocaine is preferably used since it provides a superior degree ofpain relief or analgesia for an extended period of time. The compositionis implanted into a bodily cavity or applied to a tissue or oral mucosa.

Compositions and methods for delivering a drug for preventing bacterialinfections are reported in PCT International Publication No. WO2009/073658 to Trilogic Pharma LLC. The composition comprises water,copolymer, xanthan gum and an antibiotic, an anesthetic, or ananalgesic. The composition is implanted into open cavities of humantissue including periodontal pockets, surgical incisions and openwounds.

Compositions and methods for preparing a local anesthetic in base formin order to obtain topical anesthesia through skin are reported in U.S.Pat. No. 4,529,601 to Astra Lakemedel Aktiebolag and 4,562,060 to AstraLakemedel Aktiebolag (EMLA® cream). The composition comprises a mixtureof lidocaine and prilocaine in the form of its base in a weight ratio of1:1 (2.5% and 2.5%) with purified water (92%), which delivers thetopical anesthetic through the skin. However, it takes at least 60minutes for the anesthetic to take effect and an occlusive dressingafter an application of the cream is necessary.

Fast acting compositions of topical transdermal anesthetics are reportedin U.S. Pat. No. 5,993,836 to Castillo. The composition comprises aeutectic mixture of lidocaine and prilocaine in a weight ratio of about3:1 in a lipophilic base. The composition takes effect in as little as10-40 minutes without occlusive dressing for incision, excision,ablation, vaporization and coagulation of body soft tissues in medicalspecialties including aesthetic (dermatology and plastic surgery),podiatry, otolaryngology (ENT), gynecology, neurosurgery, arthroscopy(knee surgery) and invasive and endoscopic general surgery. The averagedesensitization period of the composition is 180 minutes.

Despite these existing treatments as indicated above there remains aneed for topical anesthetics, particularly for use in chronic openwounds to reduce the debridement pain. Accordingly, it is an object ofthe present invention to provide a topical anesthetic which reduces thedebridement pain. Another object of the present invention is to providea topical anesthetic which exhibits a consistent anesthetic effect withno significant patient to patient variability. Yet another object of thepresent invention is to provide a topical anesthetic which has apredictable duration of anesthetic effect.

SUMMARY OF THE INVENTION

After extensive research and experimentation, the inventors haveunexpectedly discovered that by formulating a topical anesthetic into apoloxamer gel/jelly base, they can reduce debridement pain, increase theduration of pain relief, potentially reduce the frequency of narcoticanalgesic need, and thereby provide more effective treatment to chronicopen wounds, particularly those in non-mucosal tissue. Surprisingly,they have discovered that slowing the release of lidocaine from theirgel or ointment, using a poloxamer of the present invention, providesthe same relief as more quickly releasing formulations, and for longerperiods of time.

Thus, in a first principal embodiment, the invention provides a methodof treating pain comprising applying to an open wound a topical dosageform comprising from 2 to 5% lidocaine, wherein said dosage formreleases less than 75% of its lidocaine at 30 minutes and less than 90%of its lidocaine at 60 minutes when tested in a USP Apparatus 1 (paddle)at 50 rpm in 500 ml of an acetic acid/sodium acetate buffer, pH 4.0 at32° C.

In a second principal embodiment the invention provides a method oftreating debridement pain in a chronic open wound in non-mucosal tissue,comprising: (a) debriding the chronic open wound; (b) topically applyingto the chronic open wound a gel/jelly comprising: (i) from 70 to 90weight parts of water or a mixture of water and a humectant selectedfrom glycerine, glycerol, polyethylene glycol, and combinations thereof;(ii) from 10 to 25 weight parts of a copolymer having the followingblock structure: HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H, wherein the ratio of a:b is from 2:1 to 4:1,and the molecular weight of said copolymer is from 9000 to 16000; (iii)from 0.1 to 3.0 weight parts of xanthan gum; and (iv) from 2.0 to 5.0weight parts of an anesthetic; (c) applying an occlusive bandage to thechronic open wound; (d) removing the occlusive bandage from the chronicopen wound; and (e) debriding the chronic open wound.

In a third principal embodiment, the invention provides a method of moregenerally treating pain in a chronic open wound in non-mucosal tissue ina patient in need thereof, comprising topically applying to the chronicopen wound a gel/jelly comprising: (i) from 70 to 90 weight parts ofwater or a mixture of water and a humectant selected from glycerine,glycerol, polyethylene glycol, and combinations thereof; (ii) from 10 to25 weight parts of a copolymer having the following block structure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H, wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; (iii) from 0.1 to 3.0 weight parts ofxanthan gum; and (iv) from 2.0 to 5.0 weight parts of an anesthetic.

Additional advantages of the invention are set forth in part in thedescription that follows, and in part will be obvious from thedescription, or may be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several embodiments of theinvention and together with the description serve to explain theinvention.

FIG. 1 shows the change in Numeric Rating Scale (NRS) pain scoresreported by patients participating in an experiment of Example 2 overone week after the application of lidocaine gel in TRI-726 matrix(MP-601 gel).

FIG. 2 shows the change in pain intensity difference (NRS pain scoresnormalized to baseline) over one week after the application of MP-601gel, as reported in Example 2.

FIG. 3 reports the dissolution profile of an exemplary formulation ofthe present invention compared to two commercially availableformulations, Astero™ (Gensco Pharma, Miami, Fla.) and Regenecare™ (MPMMedical, Inc., Irving, Tex.).

DETAILED DESCRIPTION

Definitions and Use of Terms

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains. Thereferences disclosed are also individually and specifically incorporatedby reference herein for the material contained in them that is discussedin the sentence in which the reference is relied upon.

As used in the specification and claims, the singular forms a, an, andthe include plural references unless the context clearly dictatesotherwise. For example, the term “a pharmaceutically acceptable salt”refers to one or more pharmaceutical acceptable salts for use in thepresently disclosed formulations and methods.

When used herein the term “about” will compensate for variabilityallowed for in the pharmaceutical industry and inherent inpharmaceutical products, such as differences in product strength due tomanufacturing variation and time-induced product degradation. In oneembodiment the term allows for any variation which in the practice ofpharmaceuticals would allow the product being evaluated to be consideredpharmaceutically equivalent or bioequivalent to the recited strength. Inanother embodiment the term allows for any variation within 5% of therecited strength or concentration of the formulation.

The terms “treating” and “treatment,” when used herein, refer to themedical management of a patient with the intent to cure, ameliorate,stabilize, or prevent a disease, pathological condition, injury, ordisorder (collectively “disorder”). This term includes active treatment,that is, treatment directed specifically toward the improvement of adisorder, and also includes causal treatment, that is, treatmentdirected toward removal of the cause of the associated disorder. Inaddition, this term includes palliative treatment, that is, treatmentdesigned for the relief of symptoms rather than the curing of thedisorder; preventative treatment, that is, treatment directed tominimizing or partially or completely inhibiting the development of thedisorder; and supportive treatment, that is, treatment employed tosupplement another specific therapy directed toward the improvement ofthe disorder.

As used herein, “therapeutically effective amount” refers to an amountsufficient to elicit the desired biological response. Thetherapeutically effective amount or dose will depend on the age, sex andweight of the patient, and the current medical condition of the patient.The skilled artisan will be able to determine appropriate dosagesdepending on these and other factors in addition to the presentdisclosure.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.“Pharmaceutically acceptable salts” means salts that arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity.

When a weight of an active ingredient is given without reference to thefree base or salt of the active ingredient, it will be understood thatthe weight can refer to the weight of the free base or the weight or theentire salt. In like manner, when the molecule can exist as a hydrate,and the weight of the molecule is given, it will be understood that theweight refers to the weight of the molecule without the waters ofhydration.

When ranges are expressed herein by specifying alternative upper andlower limits of the range, it will be understood that the endpoints canbe combined in any manner that is mathematically feasible. Thus, forexample, a range of from 50 or 80 to 100 or 70 can alternatively beexpressed as a series of ranges of from 50 to 100, from 50 to 70, andfrom 80 to 100. When a series of upper bounds and lower bounds arerelated using the phase and/or, it will be understood that the upperbounds can be unlimited by the lower bonds or combined with the lowerbounds, and vice versa. Thus, for example, a range of greater than 40%and/or less than 80% includes ranges of greater than 40%, less than 80%,and greater than 40% but less than 80%.

When percentages, concentrations or other units of measure are givenherein, it will be understood that the units of measure are weightpercent unless otherwise stated to the contrary.

Mucosal tissues are defined groups of very similar cells gatheredtogether to cover the inside surface of parts of the body such as thenose and mouth and to produce mucus to protect them. Thus, non-mucosaltissues refer to tissues which do not satisfy the above definition suchas skin.

Discussion of Principal Embodiments

The invention can be defined based on several principal embodimentswhich can be combined in any manner physically and mathematicallypossible to create additional principal embodiments.

In a first principal embodiment, the invention provides a method oftreating pain comprising applying to an open wound a topical dosage formcomprising from 2 to 5% lidocaine, wherein said dosage form releasesless than 75% of its lidocaine at 30 minutes and less than 90% of itslidocaine at 60 minutes when tested in a USP Apparatus 1 (paddle) at 50rpm in 500 ml of an acetic acid/sodium acetate buffer, pH 4.0 at 32° C.

In a second principal embodiment the invention provides a method oftreating a debridement pain in a chronic open wound in non-mucosaltissue in a patient in need thereof, comprising: (a) debriding thechronic open wound; (b) topically applying to the chronic open wound agel/jelly comprising: (i) from 70 to 90 weight parts of water or amixture of water and a humectant selected from glycerine, glycerol,polyethylene glycol, and combinations thereof; (ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H, wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; (iii) from 0.1 to 3.0 weight parts ofxanthan gum; and (iv) from 2.0 to 5.0 weight parts of an anesthetic; (c)applying an occlusive bandage to the chronic open wound; (d) removingthe occlusive bandage from the chronic open wound; and (e) debriding thechronic open wound.

In a third principal embodiment the invention provides a method oftreating pain in a chronic open wound in non-mucosal tissue in a patientin need thereof, comprising: topically applying to the chronic openwound a gel/jelly comprising: (i) from 70 to 90 weight parts of water ora mixture of water and a humectant selected from glycerine, glycerol,polyethylene glycol, and combinations thereof; (ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)H, wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; (iii) from 0.1 to 3.0 weight parts ofxanthan gum; and (iv) from 2.0 to 5.0 weight parts of an anesthetic.

The invention can further be understood with reference to varioussubembodiments which can modify any of the principal embodiments. Thesesubembodiments can be combined in any manner that is both mathematicallyand physically possible to create additional subembodiments, which inturn can modify any of the principal embodiments.

Discussion of Dissolution Subembodiments

Any of the embodiments or subembodiments of the present invention canfurther be defined in terms of the dissolution characteristics of thetopical dosage form. Thus, in various subembodiments the dosage formreleases less than 75% of its lidocaine at 30 minutes and less than 90%of its lidocaine at 60 minutes when tested in a USP Apparatus 1 (paddle)at 50 rpm in 500 ml of an acetic acid/sodium acetate buffer, pH 4.0 at32° C.

In other subembodiments the dosage form releases less than 60% of itslidocaine at 30 minutes and less than 75% of its lidocaine at 60 minuteswhen tested in a USP Apparatus 1 (paddle) at 50 rpm in 500 ml of anacetic acid/sodium acetate buffer, pH 4.0 at 32° C.

In still further subembodiments the dosage form releases less than 55%of its lidocaine at 30 minutes and less than 70% of its lidocaine at 60minutes when tested in a USP Apparatus 1 (paddle) at 50 rpm in 500 ml ofan acetic acid/sodium acetate buffer, pH 4.0 at 32° C.

Discussion of Formulation Subembodiments

Any of the embodiments or subembodiments of the current invention canfurther be understood in terms of the formulation use to make thetopical dosage form.

One of the preferred characteristics of the dosage forms used in themethods of the present invention is their gel temperature. Thus, invarious subembodiments the dosage form is characterized by a geltemperature that is between room temperature and the body temperature ofthe patient.

Thus, in one particular subembodiment the topical dosage form is anointment or gel comprising: (i) from 70 to 90 weight parts of water or amixture of water and a humectant selected from glycerine, glycerol,polyethylene glycol, and combinations thereof; (ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H, wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; (iii) from 0.1 to 3.0 weight parts ofxanthan gum; and (iv) from 2.0 to 5.0 weight parts of lidocaine.

The thickening agent is also an important component of the formulation,for ensuring the stability of the formulation and its utility in medicalapplications. The thickening agent preferably yields a clearformulation, yet is easily processed to produce a product withappropriate viscosity and handling characteristics. Suitable thickeningagents include, for example, cellulose derivatives, natural gums, andinorganic compounds. More particular examples include methyl cellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, alginates, guar gum,pectin, aluminum silicate, magnesium aluminum silicate, silica, andcombinations thereof. A preferred thickening agent is xanthan gum,preferably from 0.1 to 2.5 weight parts, from 0.2 to 1.5 weight parts,most preferably 0.5 weight parts.

Other subembodiments are defined by the anesthetic chosen for theformulation, and the proportion of anesthetic chosen for theformulation. Suitable anesthetics include, for example, benzocaine,prilocaine, tetracaine, bupivacaine, lidocaine, and theirpharmaceutically acceptable salts. A particularly preferred anestheticis lidocaine, or one of its pharmaceutically acceptable salts.

These anesthetics can be present in any proportion equaling atherapeutically effective dose, but is preferably present in an amountof from 2.0 weight parts to 5.0 weight parts, with 3.0 to 4.5 weightparts or 4.0 weight parts being particularly preferred, particularly forlidocaine.

The formulation can also include a preservative such as benzyl alcoholor can be provided sterilized without benzyl alcohol.

The formulations also benefit from the addition of a pH adjusting agentto prevent hydrolysis of the lidocaine. The pH of the formulations willpreferably be from 3 to 6 adjusted with the pH adjusting agents orbuffers. A preferred pH adjusting agent is citrate buffer, preferablyfrom 25 to 100 mM. Alternative buffers are well known in the art andinclude, for example, acetate and phosphate buffers.

The formulations are aqueous-based formulations, preferably containingfrom 70 to 90 weight parts water, more preferably from 70 to 80 weightparts of water. The water used in the formulations is of apharmaceutically acceptable grade. It is also possible to substitutevarious humectants for the water, such as glycerine, glycerol andpolyethylene glycol, in amounts preferably between 5 and 15 weightparts. Thus, while the formulations of the present invention commonlycontain from 70 to 90 weight parts of water, they may also contain from55 to 85 weight parts water and from 5 to 15 weight parts of a humectantsuch as glycerine, glycerol, or polyethylene glycol, wherein the totalweight parts of water and humectant preferably add up to from 70 to 90weight parts.

The formulations may be based upon a copolymer. A preferable copolymeris a poloxamer having an ethylene oxide/n-propylene oxide block polymerstructure, random or ordered. The ethylene oxide preferably may be inmolar excess to the n-propyl oxide, and the ratio of ethylene oxide ton-propyl oxide units (i.e. a:b) may be from 2:1 to 4:1. The preferableblock copolymer having the structure ofHO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H. The structureconsists of a hydrophobic central core of propylene oxide (representedby “b” in the above figure), flanked by hydrophilic ethylene oxide(represented by “a” in the above figure) on both sides. The molecularweight of the copolymer may be from 5000 to 25000. In some instances,the molecular weight of the copolymer may be from 9000 to 16000. The sumof the two a's preferably is from 50 to 500, from 100 to 300, from 150to 250, or most preferably 200. b is preferably from 30 to 100, from 50to 80, from 60 to 70, or most preferably 65. The ratio of the 2 a's to bis preferably from 2:1 to 4:1. The formulation preferably is from 10 to20 weight parts of the copolymer.

The formulation may also be defined by several chemical characteristics,including a gel temperature that is between room temperature and thebody temperature of a patient, e.g., 37° C. The formulation may have aviscosity at room temperature of from 200,000 to 500,000 cps, morepreferably from 100,000 to 1,000,000 cps. In addition, the formulationmay include no component other than the above described that may changethe viscosity of the pharmaceutical formulation at room temperature(i.e. by more than 100,000, 50,000 or 10,000 cps).

Methods of Treatment

The formulations of the present invention can be used in any method thattopical anesthetics have historically been used, although they haveparticular utility in lidocaine applications. The formulations have beenfound effective for inducing local anesthesia on the chronic open woundswhich cause pain. The formulations induce local anesthesia, and they doso without inducing significant irritation.

Thus, in various subembodiments the invention provides a method for thetreatment of debridement pain. In further subembodiments the inventionprovides a method of treating pain in a chronic open wound innon-mucosal tissue, such as skin, in a patient in need thereof,comprising debriding the chronic open wound, topically applying to thechronic open wound a gel/jelly or ointment comprising the dosage form ofthe present invention, applying an occlusive bandage to the chronic openwound, removing the occlusive bandage from the chronic open wound, anddebriding the chronic open wound. Preferably, the removal step occurs atleast 24, 48, 72 hours, 96 hours or 120 hours after the applying thegel/jelly or ointment to effectively reduce pain arising from theremoval step.

In still further subembodiments the invention provides a methodcomprising topically applying a gel/jelly or ointment to the debridedopen wound and applying an occlusive bandage to the debrided open wound.

In particularly preferred subembodiments the methods are used to treatpain, particularly debridement pain, in non-mucosal tissue such as skin.Thus, in additional subembodiments the methods are used to treat pain,particularly debridement pain, in venous leg ulcers, diabetic leg/footulcers, abdominal wounds, vasculitic ulcers, abrasions, burns andpressure ulcers. As noted in this document, the subembodiments areuseful for treating debridement pain arising more than 24, 48, 72 hours,96 hours or 120 hours after the application of the dosage form.

The invention provides a method to use a Numeric Rating Scale (NRS) toreport pain relief.

Methods of Manufacture

The formulations of the present invention can be manufactured usingconventional manufacturing techniques as described, for example, inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (22d edition), althoughseveral discoveries have been made to improve their manufacture.

EXAMPLES

In the following examples, efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.) but someerrors and deviations should be accounted for. The following examplesare put forth so as to provide those of ordinary skill in the art with acomplete disclosure and description of how the methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention.

Example 1. Example Pharmaceutical Formulation

The table below illustrates an example of pharmaceutical formulation ofthe present invention. The table below is purely exemplary of theinvention and is not intended to limit the scope of what the inventorsregard as their invention. Unless indicated otherwise, parts are partsby weight.

TABLE 1 Example Pharmaceutical Formulation 1A 1B Raw material % (w/w) %(w/w) Poloxamer F127, USP 16.00 16.00 Xanthan gum, USP 0.50 0.50Lidocaine HCl, USP 4.00* 4.00* Citric acid monohydrate, USP 0.39 0.39Sod. citrate dihydrate, USP 0.93 0.93 Benzyl alcohol, USP 1.00 —Purified Water, USP qs 77.18 78.18 Total 100.00 100.00 *excluding watersof hydration; based on weight of salt

Example 2. Effectiveness of Treatment

In an attempt to relieve pain in patients with chronic open wounds andto reduce the number of narcotic medications prescribed, patients weretreated with one direct application of ˜5 mL of the gel/jelly containing4% lidocaine in TRI-726 matrix (MP-601 gel). The evaluation included 33patients consisting of 14 men (42%) and 19 women (58%) suffering frompain due to chronic open wounds. The age range of the patients was from53 to 89 years old. 12 patients had venous leg ulcers (36%), 11 haddiabetic foot ulcers (33%), 4 had pressure ulcers (12%), 2 hadvasculitic ulcers (6%), 2 had a traumatic wound (6%), 1 had an abdominalwound (3%), and 1 had a second-degree burn (3%) (Table 2). The pain wasrated by the patient prior to the application of MP-601 gel on a NumericRating Scale (NRS), a commonly used method to assess pain and stress,graduating from 0=“no pain” to 10=“worst imaginable pain”. The durationof the pain relief and the time until the patient felt that MP-601 gelwas no longer effective were calculated from these scores. The paininformation was collected at a return visit the next week, which wasmaintained in a patient diary. The patients continuously wore standarddressings and bandages appropriate for the wound types during theevaluation.

TABLE 2 Types of Chronic Open Wound in Patients Types of Wound NumberPercentage (%) Venous Leg Ulcer 12 36.4 Diabetic Foot Ulcer 11 33.3Pressure Ulcer 4 12.1 Vasculitic Ulcer 2 6.1 Traumatic Wound 2 6.1Abdominal Wound 1 3.0 Second-Degree Burn 1 3.0

Table 3 shows the initial pain scale/score in the patients prior to theapplication of MP-601 gel. 6 patients recorded pain 10 “worst imaginablepain” (18%), 24 patients indicated 6 or more in the pain scale (72%),and no patients recorded 0 “no pain”, which suggests that theparticipating patients suffered from the severity of pain accompanied bytheir chronic wounds.

TABLE 3 Initial Pain Scale of Chronic Wound by Patients Pain Scale 1 2 34 5 6 7 8 9 10 Number of 0 0 1 3 5 1 7 6 4 6 Patient Recorded Percentage0 0 3.0 9.1 15.2 3.0 21.2 18.2 12.1 18.2

Table 4 shows the duration of the pain relief over one week after theapplication of MP-601 gel. Of all patients, 2 patients had no painrelief (6%) or were non-responsive to lidocaine. Of the 31 responderswho reported an improvement, all recorded that they felt pain relief byday 1. Approximately 94% of the responders continued to feel pain reliefby day 2. The result shows that MP-601 gel was effective in providingpain relief up to 48 hours after one application. The product waseffective in complete resolution of pain in the majority of patients forthat period of time. Over half of the responders (58%) reported theeffectiveness of the M-601 gel lasted up to 4 days, which is more thanexpected and cannot be easily explained. However, the efficacy of M-601gel to yield therapeutic benefits is provided.

TABLE 4 Duration of Pain Relief 1 2 3 4 5 6 7 Day Days Days Days DaysDays Days All Patients (33)  94% 88% 73% 55% 21% 15% 6% All Responders(31) 100% 94% 77% 58% 23% 16% 7%

FIG. 1 shows the average pain score reported by the patients over oneweek following the application of MP-601 gel. MP-601 gel was appliedonce on day 0. The average pain scores from day 1 to day 4 werestatistically significantly lower (p<0.01) compared to the baseline (day0) and from day 5 to day 7 scores.

FIG. 2 shows the average pain intensity difference (pain scoresnormalized to baseline value) over one week following the application ofMP-601 gel. MP-601 gel was applied once on day 0. The average painintensity differences from day 1 to day 4 were statisticallysignificantly lower (p<0.01) compared to the baseline (day 0) and fromday 5 to day 7 scores.

Table 5 shows a comparison of the average pain scale/score prior to andat one week after the application of MP-601 gel. The average painscale/score of all patients was 7.2 prior to the application and 6 atone week after the application. Among the responders reporting animprovement, the average pain scale was 7 prior to the application and5.8 at one week after the application. The table demonstrates that thepain experienced by the enrolled patients was lower even at one weekthan they experienced at the beginning of the study.

TABLE 5 Comparison of Average Pain Scale/score before and at One WeekAfter MP-601 Application Beginning of Study End of Study All 7.2 6Responders 7 5.8

Patients' comfort level and acceptance of MP-601 were very highthroughout the study. No adverse reactions were reported during theentire study period.

Example 3. Dissolution Testing of Representative Formulation

The formulation of Example 1 with 4% lidocaine was tested for itsdissolution properties and compared to the dissolution profiles forAstero™ (Gensco Pharma, Miami, Fla.) and Regenecare™ (MPM Medical, Inc.,Irving, Tex.). Testing was performed in a USP Apparatus 1 (paddle) at 50rpm in 500 ml of an acetic acid/sodium acetate buffer, pH 4.0 at 32° C.The testing was performed according to bioequivalence recommendationspublished by the United States Food and Drug Administration forlidocaine topical patch as of Oct. 3, 2017, except that a USP Apparatus1 was used, and the gel for each product was filled into size 00 hardgelatin capsules and placed in sinkers prior to testing.

The results are reported in Table 6 and depicted in FIG. 3.

TABLE 6 Time Astero ™ MP-601 Regenecare ™ 0 0 0 0 10 33.7399 16.024250.2084 20 78.5086 28.9541 71.2818 30 99.0963 42.3929 82.8594 60 98.994466.896 93.6216 120 99.8551 91.0855 98.4742 180 100 100 100

Other Embodiments

In further embodiments, the invention is described as follows:

(1) A method of treating pain comprising applying to an open wound atopical dosage form comprising from 2 to 5% lidocaine, wherein saiddosage form releases less than 75% of its lidocaine at 30 minutes andless than 90% of its lidocaine at 60 minutes when tested in a USPApparatus 1 (paddle) at 50 rpm in 500 ml of an acetic acid/sodiumacetate buffer, pH 4.0 at 32° C.

(2) A method of treating pain in a chronic open wound in non-mucosaltissue in a patient in need thereof, comprising: (a) debriding thechronic open wound; (b) topically applying to the chronic open wound anointment or gel comprising: (i) from 70 to 90 weight parts of water or amixture of water and a humectant selected from glycerine, glycerol,polyethylene glycol, and combinations thereof; (ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH2—CH2—O]a—[CH2—CH(CH3)—O]b—[CH2—CH2—O]a—H, wherein the ratio ofa:b is from 2:1 to 4:1, and the molecular weight of said copolymer isfrom 9000 to 16000; (iii) from 0.1 to 3.0 weight parts of xanthan gum;and (iv) from 2.0 to 5.0 weight parts of an anesthetic; (c) applying anocclusive bandage to the chronic open wound; (d) removing the occlusivebandage from the chronic open wound; and (e) debriding the chronic openwound.

(3) A method of treating pain in a chronic open wound in non-mucosaltissue, comprising: (a) topically applying to the chronic open wound anointment or gel comprising: (i) from 70 to 90 weight parts of water or amixture of water and a humectant selected from glycerine, glycerol,polyethylene glycol, and combinations thereof; (ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH2—CH2—O]a—[CH2—CH(CH3)—O]b—[CH2—CH2—O]a—H, wherein the ratio ofa:b is from 2:1 to 4:1, and the molecular weight of said copolymer isfrom 9000 to 16000; (iii) from 0.1 to 3.0 weight parts of xanthan gum;and (iv) from 2.0 to 5.0 weight parts of an anesthetic.

(4) The method of embodiment 2 or 3 wherein said dosage form releasesless than 75% of its lidocaine at 30 minutes and less than 90% of itslidocaine at 60 minutes when tested in a USP Apparatus 1 (paddle) at 50rpm in 500 ml of an acetic acid/sodium acetate buffer, pH 4.0 at 32° C.

(5) The method of any of the preceding embodiments, wherein said dosageform releases less than 60% of its lidocaine at 30 minutes and less than75% of its lidocaine at 60 minutes when tested according to claim 1.

(6) The method of embodiments 1, 3, 4, or 5, further comprising: (a)topically applying the ointment or gel to the debrided open wound; and(b) applying an occlusive bandage to the debrided open wound.

(7) The method of embodiments 1, 3, 4, or 5, further comprising: (a)debriding the chronic open wound prior to applying said dosage form; (b)applying an occlusive bandage to the chronic open wound after applyingthe dosage form; (c) removing the occlusive bandage from the chronicopen wound; and (d) debriding the chronic open wound.

(8) The method of embodiments 2 or 7, wherein said removal step occursat least 72 hours, 96 hours or 120 hours after the applying step (c),and the method is effective to reduce pain arising from said removalstep.

(9) The method of any of the preceding embodiments, wherein said topicaldosage form is an ointment or gel comprising: (i) from 70 to 90 weightparts of water, glycerine, glycerol or polyethylene glycol; (ii) from 10to 25 weight parts of a copolymer having the following block structure:HO—[CH2—CH2—O]a—[CH2—CH(CH3)—O]b—[CH2—CH2—O]a—H, wherein the ratio ofa:b is from 2:1 to 4:1, and the molecular weight of said copolymer isfrom 9000 to 16000; (iii) from 0.1 to 3.0 weight parts of xanthan gum;and (iv) from 2.0 to 5.0 weight parts of lidocaine.

(10) The method of any of embodiments 2, 3, or 4, wherein the anestheticis lidocaine or a pharmaceutically acceptable salt thereof.

(11) The method of any of embodiments 2, 3, or 9, wherein the dosageform includes from 10 to 20 weight parts of said copolymer.

(12) The method of any of embodiments 2, 3, or 9, wherein said copolymeris a poloxamer.

(13) The method of any of embodiments 2, 3, or 9, wherein the sum of a'sin the block structure of the copolymer equals 200, and b in the blockstructure has a value of 65.

(14) The method of any of embodiments 2, 3, or 9, wherein the dosageform includes from 0.1 to 2.5 weight parts of said xanthan gum.

(15) The method of any of the preceding embodiments for the treatment ofdebridement pain.

(16) The method of any of the preceding embodiments, wherein the topicaldosage form comprises from 2.0 to 4.5 weight parts lidocaine or apharmaceutically acceptable salt thereof based on the weight of the freebase.

(17) The method of any of the preceding embodiments, wherein the topicaldosage form comprises about 4.0 weight parts lidocaine or apharmaceutically acceptable salt thereof based on the weight of the freebase.

(18) The method of any of the preceding embodiments, wherein the dosageform further comprises benzyl alcohol.

(19) The method of any of the preceding embodiments, wherein the dosageform includes a buffer selected from a citrate buffer, an acetatebuffer, and a phosphate buffer.

(20) The method of any of the preceding embodiments, wherein the dosageform includes from 25 to 100 mM of a citrate buffer.

(21) The method of any of the preceding embodiments, wherein the dosageform includes from 70 to 80 weight parts of water.

(22) The method of any of the preceding embodiments, wherein the dosageform is characterized by a gel temperature that is between roomtemperature and the body temperature of the patient.

(23) The method of any of the preceding embodiments, wherein the dosageform has a viscosity at room temperature of from 100,000 to 1,000,000cps.

(24) The method of any of the preceding embodiments, wherein the dosageform contains no other component that changes the viscosity of theliquid at room temperature by more than 100,000 cps.

(25) The method of any of embodiments 1, 5, 6. 7, 8 or 9, wherein thechronic open wound is in non-mucosal tissue.

(26) The method of embodiments 2, 3, or 24, wherein the chronic openwound is selected from the group consisting of venous leg ulcers,diabetic leg ulcers, abdominal wounds, vasculitic ulcers, abrasions,burns and pressure ulcers.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

REFERENCES

-   Lok, et al. “EMLA cream as a topical anesthetic for the repeated    mechanical debridement of venous leg ulcers: A double-blind,    placebo-controlled study”, Journal of the American Academy of    Dermatology, 1999; 40(2) Part 1:208-213.-   Powers, et al., “Wound healing and treating wounds: Chronic wound    care and management”, Journal of the American Academy of    Dermatology, 2016; 74(4); 607-625.-   http://www.diabetes.org/diabetes-basics/statistics/-   Hoffman D., et al., “Pain in venous leg ulcers.” 1997, Journal of    Wound Care, 6(5):222-224.-   Phillips T., et al., “A study of the impact of leg ulcers on quality    of life: financial, social, and psychologic implications.” J Am Acad    Dermatol. 1994 July; 31(1):49-53.-   Terry Treadwell, M D., et al., “Treatment of Pain in Wounds with a    Topical Long Acting Lidocaine Ointment.” 2014.-   Price P E, Fagervik-Morton H, Mudge E J, et al., “Dressing-related    pain, in patients with chronic wounds: an international patient    perspective.” Int Wound J., 2008; 5(2):159-171.-   Woo K Y, Coutts P M, Price P, Harding K, Sibbald R G., “A randomized    crossover investigation of pain at dressing change comparing 2 foam    dressings.” Adv Skin Wound Care. 2009; 22(7):304-310.-   http://www.wisegeekhealth.com/what-is-the-difference-between-lidocaine-and-benzocaine.htm-   http://www.ehow.com/about_5398369_lidocaine-vs-benzocaine.html-   Michael F. Powell, “Stability of Lidocaine in Aqueous Solution:    Effect of Temperature, pH, Buffer, and Metal Ions on Amide    Hydrolysis”, Pharmaceutical Research, February 1987; 4(1):42-45.

The invention claimed is:
 1. A method of providing pain relief for 48hours after one application from an open wound in a patient in needthereof comprising topically applying to the open wound a topical dosageform comprising from 2 to 5% lidocaine or a pharmaceutically acceptablesalt thereof, wherein: (a) the dosage form comprises: from 70 to 90weight parts of water or a mixture of water and a humectant selectedfrom glycerine, glycerol, polyethylene glycol, and combinations thereof;from 10 to 25 weight parts of a copolymer having the following blockstructure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; and 0.2-1.5 weight parts of xanthangum; (b) said dosage form releases less than 75% of its lidocaine at 30minutes and less than 90% of its lidocaine at 60 minutes when tested ina USP Apparatus 1 (paddle) at 50 rpm in 500 ml of an acetic acid/sodiumacetate buffer, pH 4.0 at 32° C., and (c) said applying provides painrelief for 48 hours after one application.
 2. The method of claim 1,wherein said dosage form releases less than 60% of its lidocaine at 30minutes and less than 75% of its lidocaine at 60 minutes when testedaccording to claim
 1. 3. The method of claim 1, further comprising: a)debriding the open wound; b) topically applying the ointment or gel tothe debrided open wound; and c) applying an occlusive bandage to thedebrided open wound.
 4. The method of claims 1, further comprising: a)debriding the chronic open wound prior to applying said dosage form; b)applying an occlusive bandage to the chronic open wound after applyingthe dosage form; c) removing the occlusive bandage from the chronic openwound; and d) debriding the chronic open wound.
 5. The method of claim4, wherein said removal step occurs at least 72 hours, 96 hours or 120hours after the applying step (b), and the method is effective to reducepain arising from said removal step.
 6. The method of claim 1, whereinthe dosage form includes from 10 to 20 weight parts of said copolymer.7. The method of claim 1, wherein said copolymer is a poloxamer.
 8. Themethod of claim 1, wherein the sum of a's in the block structure of thecopolymer equals 200, and b in the block structure has a value of
 65. 9.The method of claim 1, for the treatment of debridement pain.
 10. Themethod of claim 1, wherein the topical dosage form comprises from 2.0 to4.5 weight parts lidocaine or a pharmaceutically acceptable salt thereofbased on the weight of the free base.
 11. The method of claim 1, whereinthe topical dosage form comprises about 4.0 weight parts lidocaine or apharmaceutically acceptable salt thereof based on the weight of the freebase.
 12. The method of claim 1, wherein the dosage form ischaracterized by a gel temperature that is between room temperature andthe body temperature of the patient.
 13. A method of providing painrelief for 48 hours after one application in a chronic open wound innon-mucosal tissue, comprising: a) topically applying to the chronicopen wound an ointment or gel comprising: i) from 70 to 90 weight partsof water or a mixture of water and a humectant selected from glycerol,polyethylene glycol, and combinations thereof; ii) from 10 to 25 weightparts of a copolymer having the following block structure:HO—[CH₂—CH₂—O]_(a)—[CH₂—CH(CH₃)—O]_(b)—[CH₂—CH₂—O]_(a)—H wherein theratio of a:b is from 2:1 to 4:1, and the molecular weight of saidcopolymer is from 9000 to 16000; iii) 0.2-1.5 weight parts of xanthangum; and iv) from 2.0 to 5.0 weight parts of lidocaine or apharmaceutically acceptable salt thereof, wherein said applying providespain relief for 48 hours after one application.
 14. The method of claim13 wherein said dosage form releases less than 75% of its lidocaine at30 minutes and less than 90% of its lidocaine at 60 minutes when testedin a USP Apparatus 1 (paddle) at 50 rpm in 500 ml of an aceticacid/sodium acetate buffer, pH 4.0 at 32° C.
 15. The method of claim 13,wherein the chronic open wound is in non-mucosal tissue.
 16. The methodof claim 13, wherein the chronic open wound is selected from the groupconsisting of venous leg ulcers, diabetic leg ulcers, abdominal wounds,vasculitic ulcers, abrasions, burns and pressure ulcers.